Project Summary/Abstract A modifiable risk factor that is highly prevalent in populations translates into a substantial number of cases that can be prevented through clinical and public health interventions targeting the risk factor. In the field of cancer research, weight cycling represents a potential modifiable risk factor that is highly prevalent but under- investigated. Albeit limited, available evidence suggests that weight cycling, characterized by repeated episodes of intentional weight loss followed by regain of weight, may promote the development and progression of cancers through the insulin pathway, particularly among individuals of normal weight who are generally conceived as healthy and at lower risk for obesity-related cancer endpoints. The Health Professionals Follow-Up Study (HPFS) and Nurses' Health Study (NHS) are among the few cohorts to have administered questionnaires specifically designed to examine health consequences of weight cycling and thus, are equipped to examine not only its effects on cancer incidence and mortality but also the following heterogeneous aspects of the relationships. With available information on weight cycling experience over different durations and timing in adulthood, Aim 1 will identify the etiologically relevant period of weight cycling, which informs the optimal timing of public health interventions. Aim 2 will examine the relationship by subtypes of weight cyclers defined by methods used to lose weight. Exercise, without caloric restriction, is not an effective method of weight loss, but it has many health benefits. By specifically comparing the risks of cancer endpoints between the two weight loss regimes (caloric restriction alone versus caloric restriction and exercise combined), this aim will identify the weight loss regime that would minimize the adverse consequences of weight cycling on cancer endpoints. Additionally, by conducting stratified analysis by smoking status, Aim 2 will adequately evaluate the true associations of weight cycling with cancer incidence and mortality, minimizing smoking from distorting or masking the associations. Aim 3 will utilize stratified analysis across three adiposity trajectories (maintain normal range, maintain overweight/obesity, and become overweight/obesity), which offers a unique opportunity to identify a novel and modifiable risk factor for individuals with normal adiposity who are generally considered to have lower baseline risk for obesity-related cancers. In summary, weight cycling represents a full picture of energy imbalance over time and thus, research on weight cycling will complement limitations of previous studies on either weight gain or intentional weight loss alone. If weight cycling is demonstrated to be an independent risk factor for cancer incidence and mortality, clinical practice and public health recommendation should emphasize sustainable weight loss when guiding individuals attempting to lose weight and discourage approaches that predispose to weight cycling.